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Timolol maleate: side effects on healthy nonglaucomatous volunteers.

As the number of military pilots over the age of 40 increases, open-angle glaucoma becomes an important aeromedical problem. Epinephrine ophthalmic solution is the only antiglaucomatotic agent in use among flying personnel. Timolol maleate, a new antiglaucomatotic agent, is a nonselective beta-blocker. This drug has a potent hypotensive effect on intraocular pressure with a minimal effect on visual functions. Our data show that it significantly decreases the pulse rate and may eventually be a basis for cardiac dysrythmias.

Adrenergic beta-Antagonists↗

Pharmacological properties of the converting enzyme inhibitor, enalapril maleate (MK-421).

Enalapril maleate (MK-421), an ethyl ester, is an angiotensin-converting enzyme (ACE) inhibitor from a novel series of substituted N-carboxymethyldipeptides. The parent diacid (MK-422) N-[(S)-1-carboxy-3-phenylpropyl]-L-Ala-L-Pro of MK-421 inhibited hog plasma ACE with an I50 of 1.2 nM. Because deesterification occurs slowly or not at all in vitro, the in vitro I50 for enalapril was 1200 nM. However, both enalapril and MK-422 were potent inhibitors of ACE by the i.v. and oral routes in rats and dogs. In rats with experimental hypertension, enalapril was most potent in those models in which the renin-angiotensin system plays a dominant role (salt restriction, two-kidney Grollman) and in models rendered renin dependent by diuretics, although blood pressure reduction did occur in low or normal renin models such as spontaneously hypertensive rats, in which inhibition of ACE as measured by the blockade of angiotensin I pressor responses bore little temporal relationship to the later fall in blood pressure after enalapril.

Administration, Oral↗

An appraisal of antihypertensive efficacy and adverse reactions with two drug regimens: enalapril maleate as part of triple therapy compared to conventional triple therapy in moderate to severe hypertension.

A randomized, double-blind, parallel treatment trial was carried out in 24 patients with moderate to severe hypertension to compare the effectiveness and tolerance of two treatment regimens in reducing and maintaining supine diastolic blood pressure below 90 mmHg. Patients in Group I received 10 to 40 mg enalapril maleate per day with the addition of 50 mg hydrochlorothiazide per day and then 250 to 1000 mg alpha-methyldopa per day, if necessary. Patients in Group II received 50 mg hydrochlorothiazide per day with the addition of 80 to 240 mg propranolol and then 100 to 200 mg hydralazine per day, if necessary. Apart from the hydrochlorothiazide dosage which was fixed, the dosage of the other active drugs was titrated incrementally until the target blood pressure level was achieved. Blood pressures, heart rate and body weight were monitored at 2-weekly intervals during 26 weeks of active therapy. In Group I, blood pressure control was achieved and maintained with enalapril alone in 9 patients, 2 patients required double therapy and 1 patient triple therapy. In Group II, 9 patients required double therapy, 2 triple therapy, and only 1 patient received monotherapy. Supine and erect blood pressure control was comparable in both groups. There was, however, a significant decrease in supine heart rate in patients in Group II. More importantly, 8 of the 12 patients in Group II experienced non-life threatening adverse reactions (4 were hypokalaemic and required supplementary potassium, 2 had cold hands and feet, 1 man had sexual dysfunction and 1 acute gout) and no adverse reactions were reported by Group I patients.

Adult↗

[Comparative antiallergic and anti-inflammatory action of F1865, mepyramine maleate, desonide and disodium cromoglycate after cutaneous administration].

The actions of F 1865 (ethyl 4' methoxy 4 phenyl thiazolyl 2 oxamate), an inhibitor of the release of histamine from mast cell, desonide, a corticosteroid, mepyramine maleate, an anti-H1 antihistaminic, and disodium cromoglycate were compared after cutaneous application in various experimental models of allergy and inflammation. F 1865 decreased IgE- and IgG-dependent passive cutaneous anaphylaxis in rats at doses having no effect on histamine- and serotonin-induced capillary permeability. Disodium cromoglycate showed the same activity spectrum, but its action was only found after intradermal application. The reduction of cutaneous anaphylaxis by desonide was found parallel to its inhibition of histamine effects, and to a lesser extent of serotonin effects. In the case of mepyramine, the antiallergic effect may be explained by its antihistaminic action. Desonide was highly active on cantharidin-induced non-immune inflammation and on non-immune and delayed hypersensitivity reactions induced by picryl chloride in mouse ear. Although far less active than the corticosteroid, F 1865, mepyramine and disodium cromoglycate did reduce the three types of reactions in mice. This evidenced a part played by histamine in such inflammations. Then it is likely that the inhibition of histamine release by F 1865 plays an important part in the effect of the compound observed in the various inflammations studied. However we cannot exclude actions against other mediators involved in these reactions.

Administration, Topical↗

Selective blockade of dopamine-induced vasodilation by ergonovine maleate in the vasculatures of dogs and rabbits.

In urethane anesthetized rabbits, ergonovine maleate significantly attenuated dopamine-induced systemic hypotension. Initial pressor responses to dopamine were significantly prolonged and potentiated by ergonovine. Mesenteric vasodilation elicited by dopamine in dogs was competitively inhibited by ergonovine at doses of 0.09 and 0.18 mg/kg, i.a. Failure of ergonovine to inhibit vasodilatory responses to acetylcholine or isoproterenol suggested selective blockade. These results confirm existing evidence that ergonovine selectively antagonizes peripheral dopaminergic receptors subserving vasodilation.

Acetylcholine↗

Effect of 2,4-diamino-6-(2,5-dichlorophenyl)-s-triazine maleate (MN-1695) on gastric ulcers and gastric secretion in experimental animals.

The effect of 2,4-diamino-6-(2,5-dichlorophenyl)-s-triazine maleate (MN-1695) on various experimental gastric ulcers and gastric secretion in experimental animals was compared with that of cimetidine and cetraxate. MN-1695 significantly inhibited the formation of Shay, stress-induced, indomethacin-induced, and histamine-induced ulcers and significantly accelerated the healing of acetic acid-induced gastric ulcers. MN-1695 was much more effective in suppressing stress- and acetic acid-induced ulcers than indomethacin-induced, histamine-induced or Shay ulcers. Cimetidine was effective in preventing stress- and acetic acid-induced ulcers but had no significant effect on Shay, indomethacin-induced and histamine-induced ulcers. Cetraxate was effective in preventing only stress-induced ulcers and had almost no effect on other experimental ulcers. MN-1695 inhibited secretion of gastric juice, acid and pepsin in Shay rats, but had no influence on basal and secretagogue-stimulated acid secretion in the perfused stomach of urethanized rats. These findings suggest that MN-1695 is a new type of anti-ulcer agent.

Acetates↗

Effect of 2,4-diamino-6-(2,5-dichlorophenyl)-s-triazine maleate (MN-1695) on gastric mucosal blood flow in dogs.

The effect of 2,4-diamino-6-(2,5-dichlorophenyl)-s-triazine maleate (MN-1695) on gastric mucosal blood flow ( GMBF ) and on the changes of GMBF induced by catecholamines, tetragastrin, histamine and indomethacin were investigated in anesthetized dogs. MN-1695 at doses up to 1 mumol/kg i.v. showed only a slight but prolonged increase of GMBF . MN-1695 tended to inhibit the decreases of GMBF induced by norepinephrine and the increase of GMBF induced by tetragastrin. The later phase of decreased GMBF induced by histamine was suppressed by MN-1695. However, MN-1695 had almost no effect on the increase of GMBF induced by epinephrine. MN-1695 produced a marked increase of antral mucosal blood flow which was reduced by pretreatment with indomethacin. Systemic blood pressure, respiration and the pressor responses induced by catecholamines and gastric secretagogues were not affected by MN-1695. These results suggest that MN-1695 may possess selective effects on the gastric mucosal microcirculation and that suppressive effects of MN-1695 on the GMBF decrease induced by ulcerogenic stimuli may be responsible for its anti-ulcer activities in various types of experimental gastric ulcers.

Animals↗

Cirrhosis of the liver following therapy with perhexiline maleate.

Two patients developed cirrhosis of the liver following therapy with perhexiline maleate. Liver failure and polyneuropathy caused death in one patient who had received 300 mg daily for three years. Cirrhosis was an unexpected finding in the other patient whose perhexiline dose was 200 mg daily for five years. Perhexiline should be prescribed cautiously and discontinued if liver function tests become abnormal. Monitoring of blood levels may lead to a reduction of toxicity.

Humans↗

Effect of 2,4-diamino-6-(2,5-dichlorophenyl)-s-triazine maleate (MN-1695) on gastric mucosal damage induced by various necrotizing agents in rats.

The effect of 2,4-diamino-6-(2,5-dichlorophenyl)-s-triazine maleate (MN-1695) on the gastric mucosal damage induced in rats by various necrotizing agents was compared with those of cimetidine, cetraxate and prostaglandin (PG) E2. MN-1695 at doses of 0.37 mg (1 mumol) to 3.72 mg (10 mumol)/kg, significantly decreased in a dose-dependent manner the damage indices after the application of ethanol, HCl, NaOH, 25% NaCl or boiling water. Cimetidine in doses of 12.6 mg (50 mumol) to 126 mg (500 mumol)/kg was effective only against HCl-induced damage. Cetraxate in doses of 34.2 mg (100 mumol) to 342 mg (1 mmol)/kg was effective against damage due to ethanol, HCl, 25% NaCl or boiling water. However, cetraxate increased the damage index of NaOH-induced injury. PGE2 in a dose of 25 micrograms (70 nmol)/kg was effective against ethanol and 25% NaCl. The histological changes of gastric mucosal cells produced by ethanol were significantly decreased by MN-1695 and PGE2. These results suggest that MN-1695 has a cytoprotective action like that of PGE2 and that this cytoprotection inhibits the development of various kinds of experimental gastric ulcers.

Animals↗

[Perhexilline maleate: relationship between side-effects, plasma concentrations and rate of metabolism (author's transl)].

In three individuals (2 male and 1 female) with severe side-effects apparently related to the regular ingestion for a period of at least 5 months of perhexiline maleate, the authors studied the rate of fall in plasma levels of the drug, of its monohydroxylated metabolite, blood transaminase and glucose levels following the interruption of therapy. The relationship between these data would indicate two hypotheses which could be tested during future studies: the manner in which the body metabolises the drug would appear to vary in relation to plasma concentration and/or hepatic involvement.

Adult↗

The effect of Timolol Maleate on tonic accommodation, tonic vergence, and pupil diameter.

The beta-adrenoceptor antagonist Timolol Maleate (0.5%) was employed topically to determine whether the resting (or "tonic") position of accommodation is a consequence of steady-state equilibrium between parasympathetic and sympathetic innervation of the ciliary muscle. Ten subjects were used, eight men and two women, with an age range of 19-37 (mean = 23.2). All subjects wore an optimum refractive correction giving visual acuities of 20/20 or better. Darkroom measurements of tonic accommodation (TA), tonic vergence (TV), and pupil diameter were determined with a Badal laser optometer , a nonius alignment device and infra-red photography, respectively. Far and near points of accommodation and oculo-motor balance tests were determined by standard optometric techniques and intraocular pressure (IOP) was measured by applanation tonometry. Both TA (mean = 1.66 D) and TV (mean = 2.10 deg) assumed intermediate resting positions in the absence of visual stimulation. A double-blind protocol between Timolol and Saline demonstrated a mean myopic shift in TA of +0.85 D over 40 min with Timolol. All other experimental parameters, apart from IOP, were unaffected by Timolol. It is concluded that sympathetic innervation to the ciliary muscle plays a significant role in determining the TA position and that this innervation is mediated by inhibitory beta adrenoceptors.

Accommodation, Ocular↗

Giant vacuoles in the lining endothelium of the human Schlemm's canal after topical timolol maleate.

The outflow system was studied by light microscopy in nine human eyes that were treated with topical timolol maleate (0.5%) prior to enucleation for malignant melanoma of the choroid. The frequency of "giant vacuoles" in the lining endothelium of Schlemm's canal and the diameter of these structures was the same in a control group of eyes as in the timolol-treated series. There was no qualitative difference between the architecture of the meshwork in the control and treated groups. These morphologic findings suggested that timolol had no direct action on the outflow apparatus and did not reflect the intraocular pressure (IOP) lowering effect of the drug. The effects of anesthesia, surgical manipulations, and fixation by immersion may have masked any subtle drug effects.

Aqueous Humor↗

[Acid lysuride maleate in the prevention of migraine headache. Clinical experience].

Clinical experience of lysuride maleate acid in the treatment of 88 patients with occasional and 12 patients with chronic headache is reported. After 3-5 months observations the treatment was judged effective (excellent, good, satisfactory) in 72% of the cases and ineffective (poor, nil) in 28%. Side effects were few and short-lived, consisting mainly of slight nausea and asthenia. In 2 cases treatment was suspended as ineffective (in the patient's opinion).

Adolescent↗

Preventive treatment of serotonin-migraine with 1,3,4,14b-tetrahydro-2,7-dimethyl-2H-dibenzo(b,f)pyrazino-(1,2--d)-(1,4)-oxazepine hydrogen maleate (Org GC 94). A double-blind study.

1,3,4,14b-Tetrahydro-2,7-dimethyl-2H-dibenzo(b,f)pyrazino-(1,2-d)-(1,4)-oxazepine hydrogen maleate (Org GC 94) is an oral "antamine" preparation with anti-serotoninergic and anti-histaminic effects. Its lack of unpleasant side-effects permits protracted use for the preventive treatment of serotonin-migraine. Its chemical structure--tetracyclic ring, C-beta, C-alpha, amine in a secondary position--allows block of the receptors for serotonin and histamine. Preventive treatment with 3 x 5 mg/day of Org GC 94 for a period of 3 months can almost completely eliminate migraine attacks. 21 out of 30 patients (70%) profited from such a treatment, showing a drop from 5--30 attacks to 0--1 attack per month and normalization of high urinary serotonin, 5-HIAA or histamine levels. However, 30 patients receiving 3 x 0.5 mg or placebo daily reacted only rarely. The typical side-effects of anti-serotonin drugs, especially sedation or dizziness and hyperorexia were hardly observed. Randomization of the serotonin-migraine cases and double-blind methodology were applied throughout the trial.

Adult↗

Azatadine maleate (Zadine): evaluation in the management of allergic rhinitis.

Azatadine maleate (Zadine), a new antihistamine, was evaluated for its efficacy in 20 patients with chronic allergic rhinitis. Eighty percent of patients had symptomatic relief with a twice daily dosage of 2 mg. Sedation was volunteered as a side effect by six of the patients and was admitted by two further patients after specific questioning. A choice reaction time test gave slowing of motor function in these sedated patients. Four of the previously sedated patients experienced good symptomatic control with minimal sedation when the azatadine dose was reduced to 1 mg twice daily; slowing of motor function was not observed at this, the normal recommended dose.

Adolescent↗

[Effects of timolol maleate on untreated contralateral eyes (author's transl)].

The efficacity of installations of 0,5 p. cent timolol maleate unilaterally was statistically evaluated in 15 subjects: 5 with open-angle glaucoma, 5 with secondary glaucoma, and 5 normal subjects. A reduction in intraocular pressure was observed in all cases, not only in treated eyes, but also, though to a lesser degree, in untreated eyes. Effects were almost totally lacking on lacrimal secretion, corneal sensitivity, and pupil size in both eyes. The hypothesis is raised of possible unilateral treatment in selected patients with ocular hypertension and/or trabecular glaucoma.

Adult↗

[Effects of trimebutine maleate on interdigestive motility of the stomach and small intestine in conscious dogs].

Effects of trimebutine maleate (TM-906) on gastrointestinal motor activity of interdigestive state were studied in seven unanaesthetized dogs by means of chronically implanted force transducers. In animals which showed typical interdigestive motor pattern consisted of long lasting motor quiescence and recurring high-amplitude contractions (interdigestive contractions), intravenous infusion of TM-906 (0.6-6.0 mg/kg-hr) shortened the quiescent period. During TM-906 infusion, the number and the duration of the interdigestive contractions decreased in the gastric antrum. These effects were in a dose dependent manner. Infusion of TM-906 of 6.0 mg/kg-hr over 60 min introduced additional responses: persistent contractions different from the usual interdigestive contractions and delayed onset of the interdigestive contractions. Metoclopramide (1.8-6.0 mg/kg-hr) developed high-frequency contractions with gradually increasing amplitude and caused enhancement of the interdigestive contractions. In three animals which showed anomalous fasted motor pattern consisted of continuous low-amplitude contractions, bolus i.v. injection of TM-906 (2.0-2.5 mg/kg) introduced a transient suppression of the contractions in the antrum. Metoclopramide (1.0 mg/kg i.v.) potentiated and hyoscine-N-butylbromide (0.1 mg/kg i.v.) inhibited the contractions in all the regions.

Animals↗